SUPPLEMENT PROJECT SUMMARY/ABSTRACT This Paul B. Beeson Career Development Award supports my development as a geriatrician physician- scientist studying metabolic regulation of aging, and specifically investigation into the long-term effects of ketogenic diet on lifespan and healthspan. The core of these important data were recently published in Cell Metabolism, showing that ketogenic diet improves survival and ameliorates memory decline in aging mice. In collaboration with one of my Beeson mentors, Jorge Palop, I found that ketogenic diet suppresses the abnormal epilepsy-like EEG spikes and improves memory in the Alzheimer's Disease (AD) mouse model hAPPJ20. Ketogenic diet is a physiologically complex intervention, so we developed an innovative set of dietary and chemical tools to isolate its individual components, and have begun to apply these to study aging and AD phenotypes. In this supplemental application, I propose to use a novel toolset of diet and compound interventions to identify the component(s) of ketogenic diet that rescue visuospatial memory in the hAPPJ20 AD mouse model, confirm this mechanism in the 3xTgAD Alzheimer's mouse model, and compare it to the mechanism that preserves memory in the aging brain. This proposal is within the scope of the current award because it 1) Builds directly upon the current results showing effects of ketogenic diet in the aging brain, 2) Uses the same new methodologies that we developed to dive deeper into the findings of this award, and 3) Will permit direct comparison between the mechanism of ketogenic diet in the normal aging context of this award and in the context of AD. It is within the scope of the career development aims because it will enhance my neuroscience expertise as a geriatrician- scientist focused on the interfaces between biology of aging and the aging brain, and builds upon collaborative work with one of my existing Beeson mentors. The proposed work is tightly focused on Alzheimer's Disease, expanding upon studies in one AD mouse model and involving a second for robustness. It examines the intersection of a molecular mechanism that is broadly relevant to aging (ketone bodies as metabolic signals) with one highly specific to Alzheimer's Disease (aberrant epilepsy-like network hypersynchrony). It is highly likely to stimulate further progress on AD because the mechanistic framework it generates will directly inform translational studies involving ketone body compounds and ketogenic diets. These data will suggest criteria for designing effective interventions, provide relevant intermediate biomarkers, and permit deeper investigation into the downstream molecular targets most relevant to AD.